RU2007147420A

RU2007147420A - ORGANIC COMPOUNDS FOR TREATMENT OF INFLAMMATORY OR ALLERGIC CONDITIONS

Info

Publication number: RU2007147420A
Application number: RU2007147420/04A
Authority: RU
Inventors: Джейк АКСФОРД (GB); Джейк АКСФОРД; Урс БЭТТИГ (GB); Урс Бэттиг; Брайан КОКС (GB); Брайан Кокс; Камлеш Джагдис БАЛА (GB); Камлеш Джагдис Бала; Кэтрин ЛЕБЛАНК (GB); Кэтрин ЛЕБЛАНК; Дейвид Эндрью САНДХЭМ (GB); Дейвид Эндрью САНДХЭМ
Original assignee: Новартис АГ (CH); Новартис Аг
Priority date: 2005-05-24
Filing date: 2006-05-22
Publication date: 2009-06-27
Also published as: KR20080031200A; PT1891029E; DE602006011609D1; BRPI0611165A2; AU2006251396B2; EP1891029B1; JP2008542217A; PL1891029T3; CA2608375A1; US7678826B2; GB0510584D0; ATE454380T1; CN101228145A; MX2007014787A; WO2006125596A1; US20080200466A1; EP1891029A1; AU2006251396A1; ES2338697T3

Abstract

Compounds of formula (I) in free or pharmaceutically acceptable salt form, where R1, R2, R3, R4, R5, R6, R7, m, n, w, X, and Y have the meanings as indicated in the specification, are useful for treating conditions mediated by the CRTh2 receptor, especially inflammatory or obstructive airways diseases.

Claims

1. The compound of formula (I)

in free form or in the form of a pharmaceutically acceptable salt, in which

R ^{1 is} selected from R ^1a S—, R ^1a O— and R ^1a NR ⁹ -, where R ^1a is

where R ^1b and R ^{1c are} independently selected from hydrogen, (C ₁ -C ₈ ) alkyl, or together with the carbon atom to which they are attached form a divalent (C ₃ -C ₈ ) cycloaliphatic group,

R ² and R ^{3 are} independently selected from hydrogen, (C ₁ -C ₈ ) alkyl, or together with the carbon atom to which they are attached form a divalent (C ₃ -C ₈ ) cycloaliphatic group,

R ⁴ and R ^{5 are} independently selected from hydrogen, halogen, (C ₁ -C ₈ ) alkyl, halogen (C ₁ -C ₈ ) alkyl, (C ₃ -C ₁₅ ) carbocyclic group, nitro group, cyano group, SO ₂ R ^5a , (C ₁ -C ₈ ) alkylcarbonyl group, (C ₁ -C ₈ ) alkoxycarbonyl group, (C ₁ -C ₈ ) alkoxy group, halogen (C ₁ -C ₈ ) alkoxy group, -SR ^5b , carboxy group, carboxy ( C ₁ -C ₈ ) alkyl, amino groups, amino (C ₁ -C ₈ ) alkyl, (C ₁ -C ₈ ) alkylamino (C ₁ -C ₈ ) alkyl, di [(C ₁ -C ₈ ) alkyl] amino ( C ₁ -C ₈ ) alkyl, (C ₁ -C ₈ ) alkylamino groups, di [(C ₁ -C ₈ ) alkyl] amino groups, SO ₂ NR ^5c R ^5d , -C (O) NR ^5d R ^5f , hydroxy (C ₁ -C ₈ ) alkyl, NR ^5g SO ₂ R ^5h , NR ⁵ⁱ (CO) R ^5j , SOR ^5k (C ₆ -C ₁₅ ) of an aromatic carbocyclic group and a heterocyclic group containing from 4 to 10 atoms and including one or more heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur, R ^5a , R ^5k and R ^5b independently selected from (C ₁ -C ₈ ) alkyl, hydroxy (C ₁ -C ₈ ) alkyl, (C ₁ -C ₈ ) alkylamino (C ₁ -C ₈ ) alkyl, di [(C ₁ -C ₈ ) alkyl] amino (C ₁ -C ₈ ) alkyl, cyano (C ₁ -C ₈ ) alkyl, (C ₃ -C ₁₅ ) carbocyclic group, halogen (C ₁ -C ₈ ) alkyl and heterocyclic group containing from 4 to 10 atoms and including one or more heteroatoms selected from the group a py consisting of oxygen, nitrogen and sulfur,

R ^5c , R ^5d , R ^5e and R ^{5f are} independently hydrogen, hydroxy (C ₁ -C ₈ ) alkyl, (C ₁ -C ₈ ) alkylamino (C ₁ -C ₈ ) alkyl, di [(C ₁ -C ₈ ) alkyl] amino (C ₁ -C ₈ ) alkyl, cyano (C ₁ -C ₈ ) alkyl, (C ₃ -C ₁₅ ) carbocyclic group, halogen (C ₁ -C ₈ ) alkyl, heterocyclic group containing from 4 to 10 atoms and including one or more heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur, or together with the nitrogen atom to which they are attached form a (C ₄ -C ₁₀ ) heterocyclic group,

R ^5g and R ^{5i are} independently selected from hydrogen, (C ₁ -C ₈ ) alkyl, hydroxy (C ₁ -C ₈ ) alkyl, (C ₁ -C ₈ ) alkylamino (C ₁ -C ₈ ) alkyl, di [(C ₁ -C ₈ ) alkyl] amino (C ₁ -C ₈ ) alkyl, cyano (C ₁ -C ₈ ) alkyl, (C ₃ -C ₁₅ ) carbocyclic group, halogen (C ₁ -C ₈ ) alkyl and a heterocyclic group containing from 4 to 10 atoms and including one or more heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur,

R ^5h and R ^{5j are} independently selected from (C ₁ -C ₈ ) alkyl, (C ₃ -C ₁₅ ) carbocyclic group, heterocyclic group containing from 4 to 10 atoms and including one or more heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur, hydroxy (C ₁ -C ₈ ) alkyl, amino (C ₁ -C ₈ ) alkyl, (C ₁ -C ₈ ) alkylamino (C ₁ -C ₈ ) alkyl, di [(C ₁ -C ₈ ) alkyl] amino (C ₁ -C ₈ ) alkyl and cyano (C ₁ -C ₈ ) alkyl,

R ⁶ and R ⁷ together with the nitrogen atom to which they are attached form a heterocyclic group containing from 4 to 10 atoms, including the specified nitrogen atom as a ring heteroatom and optionally at least one ring heteroatom selected from the group consisting of nitrogen, oxygen and sulfur

R ^{8 is} selected from hydrogen, (C ₁ -C ₈ ) alkyl, (C ₃ -C ₁₅ ) cycloalkyl, (C ₁ -C ₈ ) alkyl (C ₆ -C ₁₅ ) aromatic carbocyclic group and (C ₆ -C ₁₅ ) aromatic carbocyclic group,

R ^{9 is} selected from hydrogen, (C ₁ -C ₈ ) alkyl, (C ₃ -C ₁₅ ) cycloalkyl, (C ₁ -C ₈ ) alkyl (C ₆ -C ₁₅ ) aromatic carbocyclic group, and (C ₆ -C ₁₅ ) aromatic carbocyclic group,

X is —CH ₂ -, —CH [(C ₁ -C ₈ ) alkyl] -, —CO—, —CH (OH) -, —CH [O (C ₁ -C ₈ ) alkyl] -, —C ( halogen) ₂ -, -O-, -S-, -SO-, -SO ₂ - or a chemical bond,

Y is —O—, —S—, —CH ₃ - or —NR ⁷ [(C ₁ -C ₈ ) alkyl] -,

m and n are independently from each other an integer from 0 to 3,

v is an integer selected from 1-3, and

w is an integer selected from 0-3.

2. The compound of formula (I) according to claim 1 in free form or in the form of a pharmaceutically acceptable salt, in which

R ¹ is R ^1a O-, where R ^1a is

in which R ^1b and R ^1c are hydrogen,

R ² and R ³ independently from each other are hydrogen or (C ₁ -C ₈ ) alkyl,

R ⁶ and R ⁷ together with the nitrogen atom to which they are attached form a heterocyclic group containing from 4 to 10 atoms, including the specified nitrogen atom as a ring heteroatom and optionally at least one ring heteroatom selected from the group consisting of nitrogen, oxygen and sulfur, which cycle may be unsubstituted or substituted with (C ₁ -C ₄ ) alkyl, cyano (C ₁ -C ₄ ) alkyl, (C ₁ -C ₈ ) alkylamino or di [(C ₁ -C ₈ ) alkylamino] .

R ¹² and R ¹³ independently of one another are hydrogen or halogen,

X is —CH ₂ -, —S—, —SO— or —SO ₂ -,

Y is -O-,

m and n are 1,

v is 1, and

w is an integer selected from 0-3.

3. The compound according to claim 1 in free form or in the form of a pharmaceutically acceptable salt, in which the compound corresponds to formula (Ia)

in which R ² and R ³ independently from each other are hydrogen or (C ₁ -C ₈ ) alkyl,

R ⁶ and R ⁷ together with the nitrogen atom to which they are attached form a heterocyclic group containing from 4 to 10 atoms, including the specified nitrogen atom as a ring heteroatom and optionally at least one ring heteroatom selected from the group consisting of nitrogen, oxygen and sulfur, which cycle may be unsubstituted or substituted with (C ₁ -C ₄ ) alkyl, cyano (C ₁ -C ₄ ) alkyl,

X is —CH ₂ -, —S—, —SO— or —SO ₂ -, preferably —CH ₂ -,

R ¹² and R ^{13 are} independently hydrogen or halogen, and w is 1.

4. The compound according to claim 1 selected from:

{4-chloro-2- [5-chloro-2- (1-methyl-2-oxo-2-pyrrolidin-1-yl-ethoxy) benzyl] -phenoxy} -acetic acid,

{4-chloro-2- [5-chloro-2 - ((R / S) -1-methyl-2-oxo-2-pyrrolidin-1-ylethoxy) benzyl] phenoxy} acetic acid,

{4-chloro-2- [5-chloro-2- (1-methyl-2-morpholin-4-yl-2-oxoethoxy) benzyl] phenoxy} -acetic acid,

{4-chloro-2- [5-chloro-2- (1-methyl-2-oxo-2-piperidin-1-yl-ethoxy) benzyl] phenoxy} -acetic acid,

[4-chloro-1- (2- {2- [4- (2-cyanoethyl) piperazin-1-yl] -1-methyl-2-oxoethoxy} benzyl) phenoxy] acetic acid,

(4-chloro-2- {2- [1-methyl-2- (4-methylpiperazin-1-yl) -2-oxoethoxy] benzyl} phenoxy) acetic acid,

{4-chloro-2- [2- (1-methyl-2-oxo-2-pyrrolidin-1-yl-ethoxy) benzyl] phenoxy} -acetic acid,

{4-chloro-2- [2 - ((R / S) -1-methyl-2-oxo-2-pyrrolidin-1-yl-ethoxy) benzyl] phenoxy} -acetic acid,

{4-chloro-2- [2- (1-methyl-2-oxo-2-piperidin-1-yl-ethoxy) benzyl] phenoxy} -acetic acid, and

(4-chloro-2- {5-chloro-2- [2- (4-methylpiperazin-1-yl) -2-oxoethoxy] benzyl} phenoxy) acetic acid.

5. The compound according to any one of claims 1 to 4 for use as a medicine.

6. Pharmaceutical compositions containing a compound according to any one of claims 1 to 4.

7. The use of a compound according to any one of claims 1 to 4 for the manufacture of a medicament for the treatment of diseases mediated by CRTh ₂ receptor.

8. The use of a compound according to any one of claims 1 to 4 for the manufacture of a medicament for the treatment of an inflammatory or allergic condition, especially an inflammatory or obstructive airway disease.

9. A method of obtaining compounds of formula I, as defined in claim 1, in free form or in the form of a pharmaceutically acceptable salt, comprising the steps of:

(1) (A) to obtain compounds of formula (I) in which R ¹ is

R ^1a S-, R ^1a O- or R ^1a NR ⁹ , where R ^1a is

, and all other characters meet the above definitions,

(B) cleave the ester group —COOR ⁸ in a compound of formula (I) in which R ¹ is R ^1a S—, R ^1a O— or R ^1a NR ⁹ , where R ^1a is

, R ^{8 is} selected from (C ₁ -C ₈ ) alkyl, (C ₃ -C ₁₅ ) cycloalkyl, (C ₁ -C ₈ ) alkyl [(C ₆ -C ₁₅ ) aromatic carbocyclic group] and (C ₆ -C ₁₅ ) aromatic carbocyclic group, and all other symbols meet the above definitions, and

(2) the thus obtained compound of formula (I) is isolated in free form or in the form of a pharmaceutically acceptable salt.

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